5. OMEPRAZOLE

Omeprazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole is an inhibitor of secretion of gastric acid, developed by the Swedish firm Aktiebolaget Hassle.

The product patent family for omeprazole belongs to the Haessle company, and invokes priority SE 78-4231 (14 April 1978) in Europe. In Europe, Haessle protected the invention through patent EP 005 129, in which it protected, among other claims, omeprazole or its pharmaceutically acceptable salts and pharmaceutical preparations containing them. The United States equivalents to EP 005 129 are US 4,255,431, US 4,337,257 and US 4,508,905.

The expiry date of EP 005 129 in each country, and of the equivalent patents in the same family are shown in a table below.

Although the description and claims describe omeprazole, there are no examples of salts of the compound.

The compound is very labile and decomposes easily, especially in an acid environment. This is why, when it is administered orally, it needs to be protected from the stomach’s highly acid environment. For this reason, Astra developed and patented under EP 247 903, a colour-stable oral pharmaceutical preparation containing omeprazole as an active ingredient; the preparation is characterized by being formed of a core, in the form of a small pill or tablet containing omeprazole with an alkaline reacting substance or alkaline reacting salt of omeprazole, optionally with an alkaline reacting substance. The core is covered with one or more inert separating layers containing excipients that are water soluble or rapidly disintegrating in water or water-soluble polymers used for film-coating applications, which may optionally contain pH buffering compounds between the alkaline reacting core, and an outer enteric coating.

This patent was applied for on 16 April 1987 and granted on 7 January 1993. It designates Austria, Belgium, Switzerland, Germany, Spain, France, the United Kingdom, Greece, Italy, Liechtenstein, Luxembourg, the Netherlands and Sweden.

The expiry date of EP 247 983 in each country, and of the equivalent patents of the same family, are given below.

Germany was one of the first countries in which the patent for omeprazole expired, in April 1999, and in which generic versions of Astra’s Prilosec or Mopral have been put on the market. Astra had applied for and obtained an SPC extending the patent until 21 March 2003. However, the SPC was subsequently revoked and declared null and void by a decision of the German Patent Court, dated June 1997. An appeal against the decision was lodged with the German Court of Appeal, which recently referred the case to the European Court of Justice.

The company has requested, and in some cases secured, protective measures to halt the sale of these generic versions, for alleged infringement of EP 247 983.

Astra is not only the holder of the above patents, but of many others relating to this product.

The patent claims the lithium, sodium, potassium, magnesium, calcium salts of omeprazole, a process for their manufacture, the pharmaceutical salts containing it, and its use to inhibit gastric acid secretion, to provide gastrointestinal cytoprotective effects and to treat gastrointestinal inflammatory diseases in humans and mammals and in humans.

According to the authors’ description in the patent, these novel alkaline salts of omeprazole are more stable during storage than the corresponding neutral form of omeprazole; they state, for example, that the magnesium salts are specially preferred for the preparation of tablets, while the sodium salts are preferred for the formulation of liquid pharmaceutical preparations.

This European patent and its equivalents were submitted 5 years after omeprazole or its pharmaceutically acceptable salts had been patented under EP 005 129.

Not only are separate claims made for omeprazole and its sodium or magnesium salts, but Astra again attempted to patent, under WO 99/08500 (November 1998 priority), WO 99/00380 (June 1997 priority) and WO 95/01977 (July 1993 priority), specific polymorphic forms of omeprazole, sodium omeprazole and magnesium omeprazole, respectively, characterized by having a degree of crystallinity which is higher than 70%, many years after the products had become known.

A further front in this vast field of omeprazole patents involves a push towards the development of enantiomerically pure forms of the compound or of its salts.

For example, Astra is currently in the process of registering the drug perprazole, which is an optical isomer of omeprazole. Omeprazole is a sulfoxide, and consequently a chiral compound, since sulfur is a stereogenic centre; it is a racemic mixture and perprazole is one of the two isomers of the racemic mixture.

In this case, perprazole was not patented by Astra itself but by another firm, Byk Gulden, which described and patented (+)-omeprazole and (-)-omeprazole through WO 92/08716. Although through WO 98/54171, (Swedish priority of December 1986), Astra claims S-omeprazole in a neutral form, characterized by being in a solid state.

Astra has done the same with the (+) and (-) isomers of omeprazole salts, which are protected under Astra’s PCT application relating to WO 94/27988, invoking 1993 priority. This strategy of extending product life by means of new patents continued with the submission of WO 98/54171, which describes and claims the magnesium salt of the S-enantiomer of omeprazole trihydrate or omeprazole (-)-enantiomer.

Lastly, it should be mentioned that Astra has patented new oral pharmaceutical formulations of omeprazole. Omeprazole pellets, protected by patent EP 247 983 are dosed and administered in capsule form. Astra has now designed a new form known as “MUPS” (multiunit pellet system) whereby the pellets are dosed and administered in tablet form.

In: WO 96/01623, Astra claims an oral pharmaceutical multiple unit tableted dosage form comprising tablet excipients and pellets formed by core material containing omeprazole or one of its single enantiomers or an alkaline salt of omeprazole or one of its single enantiomers, optionally mixed with alkaline compounds, covered with one or more layers, at least one of which is an enteric coating layer, whereby the enteric coating layer has mechanical properties such that the compression of the individual units mixed with the tablet excipients into the multiple unit tableted dosage form does not significantly affect the acid resistance of the individually enteric-coating layered units. A specific claim is made where the active substance is a magnesium salt of omeprazole having a degree of crystallinity which is higher than 70% as determined by X-ray powder diffraction, and where the active substance is an alkaline salt of (+) omeprazole or (-) omeprazole, preferable a magnesium salt.

This patent, which was applied for on 7 June 1995, designates, inter alia, Australia, Brazil, Canada, the Slovak Republic, the Czech Republic, China, Korea, the United States (US 5,817,338), Finland, Hungary, Japan, Mexico, Norway, Russia and Singapore. There is also an equivalent in South Africa.

The new pharmaceutical form presents no tangible advantage. Its purpose is probably to eliminate competition from alternative products produced by competitors.

In Germany and in some 20 other countries, Astra has already withdrawn the capsules containing omeprazole pellets from the market and has replaced them with the MUPS tablets. As a result, when the product patent for omeprazole expires, the generic products will have no reference on the market; this hinders or may hinder the processing and/or approval of the generic product by the relevant health authority. Some health authorities have already declared that they will not authorize generic versions of products the original form of which is no longer on the market, even if it has been present recently.

AstraZeneca itself has stated, according to the journal Scrip (issue No. 2497 of 10 December 1999) that the launch of the new MUPS formulation has led to a revitalization of the Losec brand, and was a further barrier to generic entry. Losec MUPS has been launched in around 20 countries.

In practice, this strategy is also designed to prevent parallel imports. It is common for Losec to be introduced into northern Europe from other cheaper markets in southern Europe. For example, withdrawing Losec in the United Kingdom and replacing it with MUPS prevents parallel imports of Losec, because the code of ethics of British pharmaceutical chemists stipulates that unless a prescription indicates the generic name of the compound, a chemist will not dispense an imported medicament if the name is different from that on the prescription (see, Scrip, No. 2494, 1 December 1999).

OMEPRAZOLE

COUNTRY

Product patent or patent for the equivalent processExpiry date

Pellets Patent Expiry date

Germany

EP 005.129 a03/04/199921/03/2003*

EP 247.983; EP 496.437 216/04/2007

Argentina

Unpatented

AR 240.25030/03/2005

Austria

AT 389.995 b14/08/2007

EP 247.98316/04/2007

Austria

AT 375.365 c14/12/2001

EP 496.43716/04/2007

Austria

AT 374.471 d14/09/2001 **

Australia

AU 529.65410/04/95***

AU 601.97422/04/2007

Belgium

EP 005 12916/11/2002*

EP 247 983; EP 496 43716/04/2007

Brazil

Unpatented

Unpatented

Bulgaria

Unpatented

Unpatented

Canada

CA 1,127,15806/07/99

CA 1,292,69303/12/2008

China

Unknown

CN 1,020,85230/04/2002

Cyprus

CY 1,23203/04/99

CY 1,81016/04/2007

Korea

Unknown

KR 91/457929/04/2007

Croatia

Unknown

HR 92/085401/01/2002

Cuba

Unpatented

Unpatented

Denmark

DK 150,510(11/04/99)****

DK 169,98828/04/2007

Egypt

Unpatented

Unpatented

Spain

Unpatented,

ES 2,006,457; ES 2,091,97116/04/2007

Finland

FI 65,06721/03/2003*

FI 90.39329/04/2007

Philippines

Unpatented

Unpatented

France

EP 005 12914/04/2004*

EP 247 983; EP 496 43716/04/2007

United Kingdom

EP 005 12914/04/2002*

EP 247 983; EP 496 43716/04/2007

Greece

Unpatented

EP 247 983; EP 496 43716/04/2007

Hong Kong

HK 84/0015203/04/99

HK 94/135216/04/2007

Honduras

Unknown

Unknown

Netherlands

EP 005 12915/11/2002*

EP 247 983; EP 496 43716/04/2007

Hungary

HU 179,02213/04/99

HU 196,70829/04/2007

India

Unpatented

Unpatented

Indonesia

Unknown

Unknown

Ireland

IE 48,37015/04/2002*

IE 61,41627/04/2007

Israel

Unpatented

IL 82,91118/06/2007

Italy

EP 00512901/03/2010*

EP 496 43716/04/2007

Italy

EP 247 98301/03/2010*

Japan

JP 60/034956; JP 63/05319103/01/2004;14/04/99***

JP 05/06980730/04/2007

Latvia

LV 93/853; LV 93/883;LV 93/881; LV 93/882 13/04/99

LV 10.35729/04/2007

Liechtenstein

Unpatented

EP 247.983; EP 496.43716/04/2007

Lithuania

Unknown

LT 3,69928/12/2008

Luxembourg

EP 005.12916/11/2002*

EP 247 983; EP 496 43716/04/2007

Malaysia

MY 85/7403/04/99

Unpatented

Morocco

Unknown

Unknown

Mexico

MX?03/04/99

Unpatented

Norway

NO 152,21610/04/99

NO 174,23929/04/2007

New Zealand

NZ 190,20317/04/99

NZ 220,09626/04/2007

Poland

Unpatented

PL 151.63129/04/2002

Portugal

Unpatented

PT 8478529/04/2007

Czech Republic

CZ 261,851; CZ 261,872CZ 261,873; CZ 261,87413/04/94

Unpatented

Slovak Republic

SK 261,851; SK 261,872SK 261,873; SK 261,87413/04/94

Unpatented

Romania

Unpatented

Unknown

Singapore

SG 83/0063303/04/99

SG 94/154216/04/2007

Sweden

EP 005 12904/02/2003 *

EP 247 983; EP 496 43716/04/2007

Switzerland

EP 005 12903/04/99

EP 247 983; EP 496 43716/04/2007

South Africa

ZA 79/0158602/04/99

ZA 87/237831/03/2007

Turkey

Unpatented

Unpatented

Soviet Union

SU 873,879; SU 873,880;SU 878,196; SU 895,29213/04/99

SU 1,820,83729/04/2007

Ukraine

UA 4909; UA 4910;UA 4776; UA 490813/04/99

USA

US 4,255,43105/04/2001

US 4,786,50520/04/2007

Yugoslavia

Unpatented

YU 46,19201/01/2002

Notes: The data for the table are taken from data bases (WPI, INPADOC, CIBEPAT, NEW PORT and DRUGPAT) which do not cover 100% of the patent data for the countries listed; these data need to be reconfirmed by patent data from the countries themselves. Moreover, the expiry dates for the patents are simply indicative, and also need to be confirmed by data from the countries.

* SPC extension

** SPC requested

*** Possible extension

**** SPC refused

a SPC for sodium omeprazole, 21 March 2003; SPC for omeprazole refused and under appeal.

To sum up, this case illustrates the use of a wide range of methods for broadening and extending patent protection, including the use of patent protection for polymorphs, isomers and pharmaceutical formulations.